STRUCTURE-ACTIVITY-RELATIONSHIPS OF LACTONE RING-OPENED ANALOGS OF THE ANTIMALARIAL 1,2,4-TRIOXANE ARTEMISININ

1,2,4-Trioxane benzylic ethers 8a-e were prepared as simplified, tricy clic versions of the clinically used tetracyclic antimalarial drug art emisinin (1). Five additional artemisinin analogs (9-11) were prepared . Neither water solubility (analogs 8e and 11b) nor chelating ability (analogs 9 and 10), however, produced trioxanes of especially high in vitro antimalarial activity. Trioxane fluorobenzyl ether 8b is the mos t active in this series (more active than artemisinin) against Plasmod ium falciparum parasites in vitro, with substantial activity also in m ice infected with Plasmodium berghei parasites and with 10 times highe r activity than artemisinin (1) in killing immature P. falciparum game tocytes.